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Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.

ABSTRACT: To explore the effects of propofol post-conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma-related gene1(BRG1) and Nuclear-related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non-PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxygenase-1(HO-1) and NADPH:quinone oxidoreductase1(NQO1) expression levels were evaluated. CMV-Brg1 mice were designed to investigate the role of Brg1 overexpression during HIRI. Brg1 and Nrf2 siRNA were used to examine the relationship between Brg1 and Nrf2/HO-1 pathways in propofol-mediated effects in a human hepatocyte(L02) hypoxia/reoxygenation(H/R) model. In patients, PPC attenuated both donor liver pathological and function injury, and reducing oxidative stress markers, compared to the NPC group, 24 hrs after surgery. PPC increased liver Brg1, Nrf2, HO-1 and NQO1 expression. In mice, PPC reduced HIRI by decreasing liver oxidative stress and activating Nrf2/HO-1 pathway, accompanied by up-regulation of BRG1 expression. BRG1 overexpression activated Nrf2/HO-1 transcription in CMV-BRG1 mice during HIRI. In vitro, PPC significantly elevated expression of Nrf2, HO-1 and NQO1, resulting in a reduction of cell DCFH-DA and 8-isoprostane levels and decreased lactate dehydrogenase levels, leading to an overall increase in cell viability. Moreover, the protective effects of propofol were partially abrogated in Nrf2-knock-down or BRG1-knock-down hepatocytes. Nrf2-knock-down drastically reduced protein expression of HO-1 and NQO1, while Brg1-knock-down decreased HO-1 expression. Propofol post-conditioning alleviates HIRI through BRG1-mediated Nrf2/HO-1 transcriptional activation.

SUBMITTER: Ge M

PROVIDER: S-EPMC5706583 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.

Ge Mian M Chen Huixin H Zhu Qianqian Q Cai Jun J Chen Chaojin C Yuan Dongdong D Jin Yi Y Yao Weifeng W Hei Ziqing Z

Journal of cellular and molecular medicine 20170727 12

To explore the effects of propofol post-conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma-related gene1(BRG1) and Nuclear-related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non-PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxyge ...[more]

PMID: 28749008

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Project description:Background and aimsAlthough type 2 innate lymphoid cells (ILC2s) were originally found to be liver-resident lymphocytes, the role and importance of ILC2 in liver injury remains poorly understood. In the current study, we sought to determine whether ILC2 is an important regulator of hepatic ischaemia/reperfusion injury (IRI).MethodsILC2-deficient mice (ICOS-T or NSG) and genetically modified ILC2s were used to investigate the role of ILC2s in murine hepatic IRI. Interactions between ILC2s and eosinophils or macrophages were studied in coculture. The role of human ILC2s was assessed in an immunocompromised mouse model of hepatic IRI.ResultsAdministration of IL-33 prevented hepatic IRI in association with reduction of neutrophil infiltration and inflammatory mediators in the liver. IL-33-treated mice had elevated numbers of ILC2s, eosinophils, and regulatory T cells. Eosinophils, but not regulatory T cells, were required for IL-33-mediated hepatoprotection in IRI mice. Depletion of ILC2s substantially abolished the protective effect of IL-33 in hepatic IRI, indicating that ILC2s play critical roles in IL-33-mediated liver protection. Adoptive transfer of ex vivo-expanded ILC2s improved liver function and attenuated histologic damage in mice subjected to IRI. Mechanistic studies combining genetic and adoptive transfer approaches identified a protective role of ILC2s through promoting IL-13-dependent induction of anti-inflammatory macrophages and IL-5-dependent elevation of eosinophils in IRI. Furthermore, in vivo expansion of human ILC2s by IL-33 or transfer of ex vivo-expanded human ILC2s ameliorated hepatic IRI in an immunocompromised mouse model of hepatic IRI.ConclusionsThis study provides insight into the mechanisms of ILC2-mediated liver protection that could serve as therapeutic targets to treat acute liver injury.Impact and implicationsWe report that type 2 innate lymphoid cells (ILC2s) are important regulators in a mouse model of liver ischaemia/reperfusion injury (IRI). Through manipulation of macrophage and eosinophil phenotypes, ILC2s mitigate liver inflammation and injury during liver IRI. We propose that ILC2s have the potential to serve as a therapeutic tool for protecting against acute liver injury and lay the foundation for translation of ILC2 therapy to human liver disease.

Dataset Information

Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.

Publications

Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.

Similar Datasets

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